Cannabis use in adolescence and young adulthood is very common in the United States. Accumulating evidence suggests that, unlike other illicit drugs, cannabis used in adolescence may be a causal risk factor for schizophrenia, and cannabis use affects the symptoms, course, and outcomes of the illness. The proposed research seeks to clarify the impact of cannabis use on the age at onset of prodromal symptoms (e.g., decline in functioning, difficulties concentrating, irritability, and sleep disturbances that precede psychosis), the age at onset of psychotic symptoms (i.e., hallucinations and delusions), and the nature of negative, cognitive, neurological, and positive symptoms of schizophrenia. The study also will determine whether or not a previously characterized gene-environment interaction} involving the catechol-O-methyltransferase (COMT) gene and pre-onset cannabis use} influences onset ages and symptomatology. The study involves hospitalized patients with a first episode of a schizophrenia-spectrum disorder, most of whom are African American. This population is of particular relevance given well-recognized ongoing healthcare disparities across ethnic groups, under-representation of African Americans in clinical research, underuse of mental health services by African Americans, and very high rates of cannabis use in this population. The specific aims of the research are: (1) to clarify the effects of cannabis use on disease onset by studying (a) age at onset of prodromal symptoms and (b) age at onset of psychotic symptoms in first-episode patients who used cannabis in the years prior to onset as well as those who did not; (2) to study the impact of cannabis use on disease phenomenology (i.e., symptoms, cognitive deficits, neurological signs) by comparing the clinical characteristics of first-episode patients who used cannabis prior to hospitalization with those who did not; and (3) to elucidate the impact of a specific gene-environment interaction on disease onset and disease phenomenology by investigating the effects of the COMT Val158Met functional polymorphism genotype, cannabis use, and their interaction on onset ages and symptom profiles of first-episode patients. The research will be conducted using extensive cross-sectional assessments of hospitalized first-episode patients whose data will be supplemented by information from family members/informants. Thorough and psychometrically sound instruments will be used to retrospectively assess past substance use. PUBLIC HEALTH RELEVANCE: Because schizophrenia can be such a devastating illness, efforts to better understand modifiable determinants of course and outcomes are crucial. Innovative aspects of this research that make it especially relevant and innovative include: (1) testing of focused hypotheses will be tested related to a specific recently discovered gene-environment interaction, (2) reliance on a predominantly African American sample, a group that is under- represented in psychiatric research despite a high prevalence of key risk factors, (3) the preventive implications related to future potential enhancements of outcomes by reducing cannabis use among adolescents who are at especially high risk, (4) measurement of all past use of all substances thoroughly and carefully, allowing for examination of potential interactions among the key variables being studied, and (5) the use of Ancestry-Informative Markers in the genetic analysis to control for potential effects of admixture and population stratification.